SU439087A1 - - Google Patents

Description

(54) METHOD FOR OBTAINING OPTICALLY ACTIVE COMPOUNDS

one

The invention relates to the removal of new, onticically active compounds that are analogues of the known prostaglandin Pb (PG Pb) and possess high physiological activity.

A known method for the preparation of dihydroprostaglandin Pij methyl ester (PG PIJ) is that prostaglapdip EI is subjected to catalytic hydrogenation followed by reduction of the 11-keto group with sodium borohydride atomic acid. The disadvantage of this method is the use of prostaglandin EH as the starting product, which is a medicinal preparation.

In addition, in a known manner, proizodiye of another group irostaglandinoi (RS.Pv).

A method for producing optically active compounds is proposed.

COOH (I)

where RI and Kr are hydrogen, methyl or ethyl, provided that at least one of the symbols RI and R2 does not denote hydrogen,

or racemates of this structural formula, which consists in the fact that in optically active or racemic compounds 111 of the general formula

ten

(P)

15

where RI and R2 are as defined above; Rs is hydrogen or tetrahydropyranyl, and the lactone oxo group is reduced to hydroxyl primer, the resulting compound is alkylated according to the synthesis with the compound of the general formula

Hal - (CH), - COOH (III)

where Hal is bromine or chlorine, and the resulting compound is either isolated, or the tetrahydronyranyl group is hydrochloride in the event that Ra has a different meaning than hydrogen.

The compounds of the formula I can also be obtained in the form of pharmacologically acceptable alkali metal or alkaline earth metal salts, for example sodium, aluminum, amines, in particular methylamine, quaternary ammonium salts, for example tetramethylammonium.

The lactone of formula II is reduced by a known method used to reduce cyclic carbonyl derivatives of prostanoic acid, using any reducing agent that does not react with the C – C bond or ester ester, preferably (tri-tri-butoxy) -aluminum hydride, or metal borohydride. The mixtures of a- and p-hydroxy-isomers of the reduction products are separated in a known manner, preferably by partition chromatography, preparative thin-layer chromatography and counter-current distribution. The lactone is reduced to lactol when cooled with diisobutyl aluminum hydride.

Lachtol is alkylated at 25 ° C with Wittig reagent prepared from 4-carboxybutyltriphenylphosphonium bromide and sodium dimethylsulfinylcarbanide.

If the Wittig reagent used is a carboxylic acid ester, for example, Br (CHENOSP (CH,), COOR,

where R4-alkyl with 1-8 carbon atoms, the compound of formula I can be obtained in the form of the corresponding ester. The compounds of formula I can also be converted into esters in a known manner, for example, using a diazoalkane.

The proposed method allows both optically active and racemic compounds to be cured. Optically active intermediates produce optically active compounds, and racemic intermediates produce the corresponding racemates. Racemic products are separated into optically active compounds in a known manner. For example, the free acid of formula I is separated by reacting this acid with an optically active base, for example brucine or strychnine, the resulting mixture of two diastereoisomers is separated in a known manner, for example, by fractional crystallization, to give separate diastereoisomeric salts.

The optically active acid of formula I is then obtained by treating the salt with an acid.

The IR spectra of the target products are obtained using a 42: 1 Perkin-Elmer IR spectrometer (with the exception of reservations using undiluted samples), NMR spectra using a Varian A-60 spectrophotometer in deuterium chloroform solutions with tetramethylsilane as an internal standard, and the data of the mass spectra - using a mass spectrometer model 21 -110 V with

high resolving power of Consolidated Elektrodynamic Corporation.

Example 1. y-Lactone Over, 5a-dioxy-2p- (3aoxy-4, 4-dimethyl-trans-: 1-octenyl) -1a-cyclopentane acetic acid.

A solution of 1.4 g of an optically active diol of formula II, 4.3 ml of dihydropyran and 0.023 g of p-toluenesulfonic acid in 30 ml of dichloromethane is stirred for 30 minutes at a temperature of 25 ° C. The resulting solution is washed with sodium bicarbonate solution, dried and concentrated in vacuo to give 3 g of the corresponding optically active tetrahydropyranyl compound of formula II.

Example 2. 3,3-Bis- (tetrahydropyranyl ether) y-lactol Za, 5a-dioxy-2p- (Zaoxy-4, 4-di1methyl - trans - 1 - octenyl) - 1a-cyclopentane acetaldehyde.

2.5 ml of diisobutylaluminum hydride in 16 ml of toluene was added dropwise to a stirred solution of 3 g of optically active tetrahydropyranyl ether obtained in example 1 in 25 ml of toluene cooled to -70 ° C, after which the mixture was stirred at -70 ° C for another 30 minutes and then carefully add a solution of 9 ml of tetrahydrofuran in 4.6 ml of water. The mixture is filtered, the filtrate is washed with brine, dried and concentrated. 2.8 g of a mixture of a-and p-hydroxy-isomers of the corresponding optically active target compound, y-lactol, are obtained. In the IR spectrum of this lactol, there is no absorption band characteristic of lactone.

Example 3. 11,15-Bis- (tetrathyropyranyl) ether 16,: 16-dimethyl-PO p2g /.

10.5 g of 4-carboxybutyltriphenylphosphonium bromide are introduced into a solution of sodium dimethylsulfinylcarbanide prepared from sodium hydride (60%, 2.0 g) and 50 ml of dimethylsulfoxide, and the mixture is stirred for 20 minutes at 25 ° C. Then a solution of 2.8 g of optically active lactol obtained in Example 2 in 90 ml of dimethyl sulfoxide is added dropwise to this reagent. The mixture is stirred for 2 hours at a temperature, then it is diluted with 30 ml of benzene. A solution of 6.4 g of sodium bisulfate in 30 ml of water is then added dropwise with cooling and stirring. The organic layer is then separated, washed with water, dried and concentrated in vacuo. The residue is chromatographed on silica gel using chloroform-methanol (10: 1) as eluent. Get 1.6 g of the corresponding optically active 11,15-bis- (tetrahydropyranyl) ether of formula I.

Example 4. 16,16-Dimethyl PG p2c, of the formula I (where RI and R2 are methyl).

18.6 ml of 67% aqueous acetic acid are poured into a solution of 0.8 g of ether prepared in Example 3, 5: 6 ml of tetrahydrofuran, and the mixture is pagrevyat 2 hours to a temperature of 55 ° C, and then concentrated in vacuo (below 1 mmHg). The residue is dissolved in benzene and chromatographed on silica gel (eluent: chloroform-methanol, 4: 1). The fractions containing the desired product according to thin-layer chromatography are combined and concentrated to give 0.34 g of the corresponding optically active compound of formula I. Mass spectrum of the trimethylsilyl derivative M + -CH3, 655.4047.

Subject invention

The method of obtaining optically active compounds of the general formula

soon

where RI and R2 are hydrogen, megyl or ethyl, provided that at least one of the CHIMBOs RI and R2 does not denote hydrogen.

6

or racemates of this structural formula, characterized in that in an optically active or racemic compound of the general formula

 0

.0

7

R,

R, u

ten

 KOH,

where RI and Ra are as defined above; Rs is hydrogen or tetrahydropyranyl,

the lactone oxo group is reduced to the hydroxyl group, the resulting compound is alkylated according to Wittig with a compound of the general formula

Hal - (SNg) - GOOH

where Hal is bromine or chlorine, and the resulting compound is either isolated or the tetrahydropyranyloxy group is saponified into hydroxyl groups if Rs has a different meaning than hydrogen.